Glioblastoma (GBM), the most common and deadliest of adult human brain tumors, has a median survival of 9-12 months despite maximum treatment. Despite significant progress in tile identification of mutations associated with GBM and the lower grade gliomas, major conceptual gaps remain in the areas of disease mechanisms and its management. Specifically, questions central to glioma pathogenesis include: 1) the tumor's cell of origin and how the state of cellular differentiation influences the oncogenic actions of prominent glioma-relevant mutations, 2) how such mutations contribute to specific biological and clinical characteristics of the disease, and 3) whether these arc required for both the genesis and maintenance of gliomas. The proposed studies will address these questions by engineering mice harboring activated oncogenes and conditional tumor suppressor gene mutations. With the aide of developmental stage specific promoters and inducible systems, it will be possible to ascertain both how the glioma-genic potential of these mutations are influenced by the state of cellular differentiation and whether continued activity of the glioma oncogenes is needed for maintenance of fully-established tumors. Specific efforts will include the analysis of mutations associated with primary GBM, e.g., activated epidermal growth factor receptor (EGFR) and loss of INK4a, as well as those mutations associated with low-grade astrocytoma, e.g., PDGF-B overexpression and loss of p53. Finally, the impact of somatic loss of INK4a and/or PTEN in the progression towards high-grade gliomas will be assessed in these models. In each of these models, tumor genesis, progression and maintenance will include a detailed work-up on the clinical, pathological, and molecular levels including transcriptional profiling and array-CGH.